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Canadian Journal of Gastroenterology &... 2022The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases...
The lung is the most common extra-abdominal metastasis site of colorectal cancer (CRC). This study aimed to investigate the genetic variation of pulmonary metastases (PM) and primary tumors in resectable CRC. The clinical data of 410 patients with PM after CRC surgery and 33 paraffin-embedded tissue samples from January 2012 to July 2019 in our hospital were collected retrospectively. Next, 450-panel gene detection technologies based on next-generation sequencing (NGS) were used to analyze the changes in the gene map and the overall variation in cancer-related genes in PM and primary tumors. After quality control, 19 samples were included in the final gene analysis. The results showed that APC (89.5%), TP53 (89.5%), and KRAS (53%) were the most common mutations in PM and primary tumors, but the gene amplification variation was enriched in primary tumors (4.6% vs. 11.4%). KRAS G12D was the most common site variation of the KRAS gene in both PM and primary tumors of CRC. There was no hotspot mutation in the TP53 locus in CRC, and the TP53 mutation in the PM was consistent with that in the primary lesion. The microsatellite instability (MSI) levels of 10 patients were MSS. The mean tumor mutation burden (TMB) of the primary tumor (5.3 muts·Mb) was slightly higher than that of metastasis (5.0 muts·Mb). In our institution, the genetic characteristics of resectable PM from CRC may be highly consistent with those of the primary tumor.
Topics: Adenomatous Polyposis Coli Protein; Colorectal Neoplasms; Humans; Lung Neoplasms; Microsatellite Instability; Mutation; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Tumor Suppressor Protein p53
PubMed: 35531124
DOI: 10.1155/2022/2033876 -
Brazilian Journal of Biology = Revista... 2021Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the...
Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the incidence of this disease has been increasing in the younger population. Both genetic and lifestyle factors may have contributed to its increased incidence and pathogenesis. Monosodium glutamate (MSG) is a food flavor enhancer that can be found in many commercial foods, and it can sometimes be used as a substitute to table salt. MSG has been investigated for its possible genotoxicity, yielding controversial results. In the present study, the effect of MSG on cell viability and its effect on expression of APC, BECN1, and TP53 genes in SW620 and SW480 colon cancer cell lines were studied. TP53 is a tumor suppressor gene that functions in modifying DNA errors and/or inducing apoptosis of damaged cells, and both APC and BECN1 genes are involved in CRC and are of importance in cellular growth and metastasis. Cancer cell viability was analyzed using MTT assay, and the results showed a significant increase in the number of viable cells after 24 h of treatment with MSG with different concentrations (0.5, 1.0, 10, 50, and 100mM). Moreover, gene expression results showed a significant increase in the expression levels of APC and BECN1 under specified conditions in both cell lines; conversely, TP53 showed a significant decrease in expression in SW620 cells. Thus, it can be concluded that MSG possibly confers a pro-proliferative effect on CRC cells.
Topics: Beclin-1; Cell Proliferation; Colonic Neoplasms; Gene Expression; Genes, p53; Humans; Sodium Glutamate; Tumor Suppressor Protein p53
PubMed: 34909835
DOI: 10.1590/1519-6984.246970 -
Middle East Journal of Digestive... Jul 2022: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic... (Review)
Review
: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic disruptions in different cancers because they can be used as a target-specific therapy. We aimed to systemically review some gene expression patterns in gastric cancer. : The current systematic review was designed and executed in 2020. Scopus, PubMed, Cochrane Library, Google Scholar, web of knowledge, and Science Direct were searched for relevant studies. A manual search of articles (hand searching), reference exploring, checking for grey literature, and seeking expert opinion were also done. : In this review, 65 studies were included, and the expression pattern of HER2/ ERBB2, ER1/Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, FGFR2 and MET was investigated. TP53, APC, KRAS, and PIK3CA mutation cumulative frequency were 24.8 (I=95.05, Q value=525.53, df=26, <0.001), 7.2 (I=89.79, Q value=48.99, df=5, <0.001), 7.8 (I=93.60, Q value=140.71, df=9, =0.001) and 8.6 (I=80.78, Q value=525.53, df=9, <0.001) percent, respectively. Overexpression was investigated for HER1/ Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, CCND1, FGFR2, MET and MYC. The frequency of TP53 and HER2/ERBB2 were 43.1 (I=84.06, Q value=58.09, df=9, <0.001) and 20.8 (I=93.61, Q value=234.89, df=15, <0.001) percent, respectively. : More research is encouraged to investigate the genes for which we could not perform a meta-analysis.
PubMed: 36619267
DOI: 10.34172/mejdd.2022.292 -
Cancer Research and Treatment Oct 2023Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific...
PURPOSE
Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.
MATERIALS AND METHODS
Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed.
RESULTS
APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations.
CONCLUSION
APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.
Topics: Humans; Prognosis; Colorectal Neoplasms; Adenomatous Polyposis Coli; Mutation; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37114476
DOI: 10.4143/crt.2023.415 -
Cancer Science Dec 2023Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can...
Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.
Topics: Humans; Genes, APC; Fibromatosis, Aggressive; Genotype; Adenomatous Polyposis Coli; Phenotype; Stomach Neoplasms; Genetic Association Studies; Mutation
PubMed: 37798255
DOI: 10.1111/cas.15945 -
Cellular and Molecular Life Sciences :... Jan 2024The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the...
The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
Topics: Humans; Axin Signaling Complex; Axin Protein; beta Catenin; Phase Separation; Mutation; Wnt Signaling Pathway; Adenomatous Polyposis Coli Protein
PubMed: 38279052
DOI: 10.1007/s00018-023-05068-0 -
BMC Biology Jan 2023Methods for the long-term in situ transduction of the unperturbed murine intestinal epithelium have not been developed in past research. Such a method could speed up...
BACKGROUND
Methods for the long-term in situ transduction of the unperturbed murine intestinal epithelium have not been developed in past research. Such a method could speed up functional studies and screens to identify genetic factors influencing intestinal epithelium biology. Here, we developed an efficient method achieving this long-sought goal.
RESULTS
We used ultrasound-guided microinjections to transduce the embryonic endoderm at day 8 (E8.0) in utero. The injection procedure can be completed in 20 min and had a 100% survival rate. By injecting a small volume (0.1-0.2 μl) of concentrated virus, single shRNA constructs as well as lentiviral libraries can successfully be transduced. The new method stably and reproducibly targets adult intestinal epithelium, as well as other endoderm-derived organs such as the lungs, pancreas, liver, stomach, and bladder. Postnatal analysis of young adult mice indicates that single transduced cells at E8.0 gave rise to crypt fields that were comprised of 20-30 neighbouring crypts per crypt-field at 90 days after birth. Lentiviral targeting of Apc mutant and wildtype mice revealed that heterozygous loss of Apc function suppresses the developmental normal growth pattern of intestinal crypt fields. This suppression of crypt field sizes did not involve a reduction of the crypt number per field, indicating that heterozygous Apc loss impaired the growth of individual crypts within the fields. Lentiviral-mediated shRNA knockdown of p53 led to an approximately 20% increase of individual crypts per field in both Apc and Apc mice, associating with an increase in crypt size in Apc mice but a slight reduction in crypt size in Apc mice. Overall, p53 knockdown rescued the reduction in crypt field size in Apc-mutant mice but had no effect on crypt field size in wildtype mice.
CONCLUSIONS
This study develops a novel technique enabling robust and reproducible in vivo targeting of intestinal stem cells in situ in the unperturbed intestinal epithelium across different regions of the intestine. In vivo somatic gene editing and genetic screening of lentiviral libraries has the potential to speed up discoveries and mechanistic understanding of genetic pathways controlling the biology of the intestinal epithelium during development and postnatal life. The here developed method enables such approaches.
Topics: Mice; Animals; Mice, Transgenic; Tumor Suppressor Protein p53; Genes, APC; Intestinal Mucosa; Stem Cells
PubMed: 36627630
DOI: 10.1186/s12915-022-01466-1 -
Journal of the Endocrine Society Sep 2020This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing... (Review)
Review
This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of , , and and of in isolated forms. somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric hybrid gene, FH-II due to germline mutations, FH-III due to germline mutations, FH-IV due to germline mutations and PA, and seizures and neurological abnormalities syndrome due to germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in , , , , and genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation.
PubMed: 32783015
DOI: 10.1210/jendso/bvaa075 -
Scientific Reports Feb 2022A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially...
A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially higher than those of the general population. The aim of the study was to determine the differences or similarities of mutation profile among low- and high-grade adenomas and in situ carcinoma with detailed follow up. We have investigated the mutation spectrum of well-known genes involved in CRC (such as APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of 96 adenomas and in situ carcinomas using a high-throughput genotyping technique. Besides, the microsatellite instability and APC and MLH1 promoter methylation were studied as well. We observed a high frequency of pathogenic variants in the studied genes. The APC, KRAS and TP53 mutation frequencies were slightly lower in adenoma samples than in in situ carcinoma samples. Further, when we stratified mutation frequency based on the grade, the frequency distribution was as follows: low-grade adenoma-high-grade adenomas-in situ carcinoma: APC gene 42.9-56.0-54.5%; KRAS gene 32.7-32.0-45.5%; TP53 gene 8.2-20.0-18.2%. The occurrence of KRAS mutation was associated with the presence of villous histology and methylation of the APC promoter was significantly associated with the presence of POLE genetic variations. However, no association was noticed with the presence of any singular mutation and occurrence of subsequent adenoma or CRC. Our data supports the multistep model of gradual accumulation of mutations, especially in the driver genes, such as APC, TP53 and KRAS.
Topics: Adenoma; Aged; Biomarkers, Tumor; Carcinoma in Situ; Colorectal Neoplasms; DNA Methylation; Female; Follow-Up Studies; Humans; Male; Microsatellite Instability; Mutation; Prognosis
PubMed: 35173208
DOI: 10.1038/s41598-022-06498-9 -
Establishing and Validating an Aging-Related Prognostic Four-Gene Signature in Colon Adenocarcinoma.BioMed Research International 2021Aging is a process that biological changes accumulate with time and lead to increasing susceptibility to diseases like cancer. This study is aimed at establishing an...
BACKGROUND
Aging is a process that biological changes accumulate with time and lead to increasing susceptibility to diseases like cancer. This study is aimed at establishing an aging-related prognostic signature in colon adenocarcinoma (COAD).
METHODS
The transcriptome data and clinical variables of COAD patients were downloaded from TCGA database. The genes in GOBP_AGING gene set was used for prognostic evaluation by the univariate and multivariate Cox regression analyses. The model was presented by a nomogram and assessed by the Kaplan-Meier curves and calibration curves. The drug response and gene mutation were also performed to implicate the clinical significance. The GO and KEGG analyses were employed to unravel the potential functional mechanism.
RESULTS
The Gene Set Enrichment Analysis result indicates that GOBP_AGING pathway is significantly enriched in COAD samples. Four aging-related genes are finally used to construct the aging-related prognostic signature: FOXM1, PTH1R, KL, and CGAS. The COAD patients with high risk score have much shorter overall survival in both train cohort and test cohort. The nomogram is then assembled to predict 1-year, 3-year, and 5-year survival. Patients with high risk score have elevated infiltrating B cell naïve and attenuated cisplatin sensitivity. The mutation landscape shows that the TTN, FAT4, ZFHX4, APC, and OBSCN gene mutation are different between high risk score patients and low risk score patients. The differentially expressed genes between patients with high score and low score are enriched in B cell receptor signaling pathway.
CONCLUSION
We constructed an aging-related signature in COAD patients, which can predict oncological outcome and optimize therapeutic strategy.
Topics: Adenocarcinoma; Age Factors; Biomarkers, Tumor; Colonic Neoplasms; Databases, Genetic; Gene Expression; Gene Expression Profiling; Humans; Models, Theoretical; Mutation; Nomograms; Prognosis; Reproducibility of Results; Transcriptome
PubMed: 34790819
DOI: 10.1155/2021/4682589